Pyrrolobenzodiazepines and conjugates thereof

Abstract

Conjugate compounds of formula (A):

wherein:

• • R² is

where R^36a and R^36b are independently selected from H, F, C_1-4 saturated alkyl, C_2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C_1-4 alkyl amido and C_1-4 alkyl ester or, when one of R^36a and R^36b is H, the other is selected from nitrile and a C_1-4 alkyl ester;

• • R⁶ and R⁹ are independently selected from H, R, OH, OR, SH, SR, NH₂, NHR, NRR′, NO₂, Me₃Sn and halo;
  • R⁷ is independently selected from H, R, OH, OR, SH, SR, NH₂, NHR, NRR′, NO₂, Me₃Sn and halo;
  • Y is selected from formulae A1, A2, A3, A4, A5 and A6:

• • L is a linker connected to a cell binding agent;
  • CBA is the cell binding agent;
  • n is an integer selected in the range of 0 to 48;
  • R^A4 is a C_1-6 alkylene group;

either

(a) R¹⁰ is H, and R¹¹ is OH, OR^A, where R^A is C_1-4 alkyl; or

(b) R¹⁰ and R¹¹ form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or

(c) R¹⁰ is H and R¹¹ is OSO_zM, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;

R and R′ are each independently selected from optionally substituted C_1-12 alkyl, C_3-20 heterocyclyl and C_5-20 aryl groups, and optionally in relation to the group NRR′, R and R′ together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered heterocyclic ring;

wherein R¹⁶, R¹⁷, R¹⁹, R²⁰, R²¹ and R²² are as defined for R⁶, R⁷, R⁹, R¹⁰, R¹¹ and R² respectively;

wherein Z is CH or N;

wherein T and T′ are independently selected from a single bond or a C_1-9 alkylene, which chain may be interrupted by one or more heteroatoms e.g. O, S, N(H), NMe, provided that the number of atoms in the shortest chain of atoms between X and X′ is 3 to 12 atoms; and

X and X′ are independently selected from O, S and N(H).

Description

[0001]The present invention relates to pyrrolobenzodiazepines (PBDs), in particular pyrrolobenzodiazepines having a linker group connected to a cell binding agent.BACKGROUND TO THE INVENTIONPyrrolobenzodiazepines[0002]Some pyrrolobenzodiazepines (PBDs) have the ability to recognise and bond to specific sequences of DNA; the preferred sequence is PuGPu. The first PBD antitumour antibiotic, anthramycin, was discovered in 1965 (Leimgruber, et al., J. Am. Chem. Soc., 87, 5793-5795 (1965); Leimgruber, et al., J. Am. Chem. Soc., 87, 5791-5793 (1965)). Since then, a number of naturally occurring PBDs have been reported, and over 10 synthetic routes have been developed to a variety of analogues (Thurston, et al., Chem. Rev. 1994, 433-465 (1994); Antonow, D. and Thurston, D. E., Chem. Rev. 2011 111 (4), 2815-2864). Family members include abbeymycin (Hochlowski, et al., J. Antibiotics, 40, 145-148 (1987)), chicamycin (Konishi, et al., J. Antibiotics, 37, 200-206 (1984)), DC-81 (Japanese Paten...

AI Technical Summary

Benefits of technology

[0048]A seventh aspect of the present invention provides a compound of the first aspect of the invention or a pharmaceutical composition of the fourth aspect of the invention for use in a method of treatment of a proliferative disease. The fifth aspect also provides the use of a compound of the fi

Problems solved by technology

The use of antibody-drug conjugates (ADC), i.e. immunoconjugates, for the local delivery of cytotoxic or cytostatic agents, i.e. drugs to kill or inhibit tumor cells in the treatment of cancer, targets delivery of the drug moiety to tumors, and intrac

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